Structure-based design and synthesis of a novel class of Src SH2 inhibitors

Buchanan, Joan L.; Bohacek, Regine S.; Luke, George P.; Hatada, Marcos; Xiao, Lu; Narula, Surinder S.; Yuan, Ruth W.; Holt, Dennis A.

doi:10.1016/s0960-894x(99)00388-1

Cited by 37 publications

(24 citation statements)

References 26 publications

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“…Peptides can also be modified with the addition of a membrane translocating sequence for delivery into a cell (44 -48). In addition, a structure-based approach can be used for optimization of the targeting properties of a peptide, such as affinity, by studying the peptide or the peptide complexed to its target (4,6,49,50).…”

mentioning

confidence: 99%

Identification of Novel Non-phosphorylated Ligands, Which Bind Selectively to the SH2 Domain of Grb7

Pero

Oligino

Daly

et al. 2002

Journal of Biological Chemistry

121

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Grb7 is an adapter-type signaling protein, which is recruited via its SH2 domain to a variety of receptor tyrosine kinases (RTKs), including ErbB2 and ErbB3. It is overexpressed in breast, esophageal, and gastric cancers, and may contribute to the invasive potential of cancer cells. Molecular interactions involving Grb7 therefore provide attractive targets for therapeutic intervention. We have utilized phage display random peptide libraries as a source of small peptide ligands to the SH2 domain of Grb7. Screening these libraries against purified Grb7 SH2 resulted in the identification of Grb7-binding peptide phage clones that contained a nonphosphorylated Tyr-X-Asn (YXN) motif. The tyrosinephosphorylated form of this motif is characteristic of Grb7 SH2 domain binding sites identified in RTKs and other signaling proteins such as Shc. Peptides that are non-phosphorylated have greater potential in the development of therapeutics because of the instability of a phosphate group in vivo. Using a biased library approach with this conserved YXN motif, we identified seven different peptide phage clones, which bind specifically to the SH2 domain of Grb7. These peptides did not bind to the SH2 domain of Grb2 (which also selects for Asn at pY ؉2 ) or Grb14, a closely related family member. The cyclic structure of the peptides was required to bind to the Grb7 SH2 domain. Importantly, the synthetic Grb7-binding peptide G7-18 in cell lysates was able to specifically inhibit the association of Grb7 with the ErbB family of RTKs, in particular ErbB3, in a dose-dependent manner. These peptides will be useful in the development of targeted molecular therapeutics for cancers overexpressing Grb7 and in the development of Grb7-specific inhibitors to gain a complete understanding of the physiological role of Grb7.

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mentioning

confidence: 99%

Identification of Novel Non-phosphorylated Ligands, Which Bind Selectively to the SH2 Domain of Grb7

Pero

Oligino

Daly

et al. 2002

Journal of Biological Chemistry

121

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“…Wider modification has seen analogous use of 2,4- [163] and 2,5-disubstituted thiazole and 1,2,4-oxadiazole [164] templates, while a benzothiazepinone scaffold (128) has been used as replacement for (pY+1/pY+2)-Glu residues, based on the ancillary status of the latter's interactions with the SH2-domain. Beneficial hydrophobic interaction with the (pY+0)-binding pocket was demonstrated in this approach by use of a monobenzyl phosphate pY+0 function [165].…”

Section: Targeting Of Sh2-domain Of Pp60 C-srcmentioning

confidence: 99%

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

Wardle¹,

Bligh²,

Hudson³

2008

CMC

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Literature publications reporting the development of organophosphorus compounds, targeting aspects of signal transduction to the titled therapeutic ends, are reviewed. With respect to extracellular targets, the development of ligands to purinergic (P2), and endothelial differentiation-gene receptors (of S1P- and LPA-receptor subtypes) is charted, along with inhibitors of the production and release of tumour necrosis factor-alpha (TNF-alpha). Reported also are inhibitors of the ectoenzymes aminopeptidase N, aminopeptidase A and dipeptidyl peptidase IV, the proteolytic enzyme thrombin, ligands to "apoptosis-receptors" and gammadelta T-cell activators. In addition, disruption of intracellular signalling chains mediated through reversible coupling of proteins via phosphorylation of Tyr residues and docking of pTyr residues in SH2-binding domains is covered. In particular, the development of ligands to SH2-binding domains in tyrosine kinases Src and lck, adaptor protein Grb2, and also ZAP70 protein are reported along with inhibitors to relevant phosphatases. SAR studies of ligands to Ins(1,4,5)-P3- and ryanodine-type receptors of intracellular Ca2+-storage organelles are described including analogues to secondary messengers cyclic-ADP-ribose (cADPR) and myo-inositol-1,4,5-triphosphate. Inhibitors of phosphatidyl inositol 3-kinase (PI3K) and sphingomyelinase are also reported, as are inhibitors of farnesyl transferase, the enzyme involved in protein-prenylation.

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“…The fact that also 5-membered rings [136,137] can be used as scaffolds, gave the opportunity to the synthesis of a series of compounds having an imidazole scaffold, incorporating a carboxamide chain (49) [138]. In order to reduce the overall charge, the (pY + 1) Glu residue was substituted with a 2-methyl group, a substitution allowed without reduction in potency [110,134,136].…”

Section: Sh2 Inhibitorsmentioning

confidence: 99%

Inhibitors for Proteins Endowed with Catalytic and Non-Catalytic Activity which Recognize pTyr

Costantino¹,

Barlocco

2004

CMC

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Reversible phosphorylation of Tyr residues in proteins plays a central role in the transduction of signals. For both SH2 domains and for protein tyrosine phosphatases (PTPs) the phosphate group of phosphotyrosine (pTyr) of peptides provides a key affinity element, but its highly charged nature and its hydrolytic lability render it unsuitable in inhibitor design. The research in the recent years has been addressed to find pTyr bioisosters devoid of the phenylphosphate moiety and more potent inhibitors with less peptidic character. Several derivatives were prepared as pTyr bioisosters, and their activity appears to depend on the nature of the substrate, peptidic or low-molecular weight compounds, in which they are placed. In the field of PTPs, the research was mainly focused on new and selective PTP1B inhibitors, possibly useful in the treatment of Type 2 diabetes. The discovery of non-peptidic low molecular weight compounds able to inhibit PTP1B, by means of docking procedures and HTS screening, and the presence of secondary binding sites on PTP1B afforded new potent and selective inhibitors; several leads devoid of negative charges were also found. To date, however, few compounds have been tested In vivo and found to show a significant activity in diabetic mouse models. Other neutral compounds, mainly quinones, were found to inhibit CD45 and Cdc25. Several papers have appeared in recent years on the discovery of new Grb2, Src, Syk, and Lck SH2 domains binding antagonists. In this field very good inhibitors derived from high affinity peptides were found, with less peptidic character and with a reduced number of negative charges; however the presence of some negative charges, especially the one present on the pTyr bioisoster moiety, seems to be indispensable. As regards Grb2, Src and Lck SH2 domains, rigidification of the starting high affinity binding peptides afforded derivatives with improved affinity; cellular activity was achieved by modification of the side chains of these inhibitors.

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Structure-based design and synthesis of a novel class of Src SH2 inhibitors

Cited by 37 publications

References 26 publications

Identification of Novel Non-phosphorylated Ligands, Which Bind Selectively to the SH2 Domain of Grb7

Identification of Novel Non-phosphorylated Ligands, Which Bind Selectively to the SH2 Domain of Grb7

Organophosphorus Compounds: Intervention in Mechanisms of Signal Transduction Relevant to Proliferative, Immunological and Circulatory Disorders

Inhibitors for Proteins Endowed with Catalytic and Non-Catalytic Activity which Recognize pTyr

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